Amy Marren

Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials

Objective Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohns disease (CD). Design We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study. Results 180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments. Conclusions Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib. Trial registration numbers NCT01393626 and NCT01393899.

Immunogenicity of biologics in inflammatory bowel disease

Crohn’s disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Treatment options include biologic therapies; however, a proportion of patients lose response to biologics, partly due to the formation of anti-drug antibodies (ADAbs). Concomitant immunosuppressive agents reduce the development of ADAbs. This review article aims to assess the immunogenicity of biologic therapies and their clinical implications. A comprehensive literature search was conducted for articles published January 2009 to August 2015 reporting immunogenicity to adalimumab (ADM), certolizumab pegol (CZP), golimumab, infliximab (IFX), ustekinumab, and vedolizumab in inflammatory bowel disease (IBD). Eligible articles were reviewed and quality assessed by independent reviewers. Overall, 122 publications reporting 114 studies were assessed. ADAbs were reported for all agents, but the percentage of patients developing ADAbs was extremely variable, with the highest (65.3%) being for IFX administration to patients with IBD. ADAb presence was frequently associated with a reduction in primary efficacy and a loss of response, and, for IFX, an increase in adverse events (AEs). Lower serum levels of ADM, CZP and IFX were seen in ADAbs-positive rather than ADAbs-negative patients; pharmacokinetic data were unavailable for other therapies. Little information was available regarding the timing of ADAb development; studies reported their detection from as early as 10–14 days up to months after treatment initiation. Biologic therapies carry an intrinsic risk of immunogenicity, although reported rates of ADAbs vary considerably. The clinical implications of immunogenicity are a concern for effective treatment; further research, particularly into the more recently approved biologics, is required.

Ulcerative Colitis Treatment Patterns and Cost of Care

OBJECTIVES To examine treatment patterns, dosing, health care resource utilization, and cost of tumor necrosis factor inhibitors (TNFi), adalimumab (ADA) and infliximab (IFX), among patients enrolled in US Humana insurance plans who have been diagnosed with ulcerative colitis (UC). METHODS This retrospective cohort study identified the first pharmacy or medical claim for ADA or IFX (from January 1, 2007, to December 31, 2014) in patients with continuous enrollment for 6 months or more preindex and 12 months or more postindex, with one or more UC diagnosis claim 6 months pre- or postindex. TNFi discontinuation was defined as a therapy gap of 56 days or more for ADA and 112 days or more for IFX. TNFi switch was defined as nonindex TNFi initiation. Health care resource utilization and costs were characterized quarterly according to treatment patterns. RESULTS The study population comprised 295 patients: mean age 50.9 years, 50.5% females, and 61.7% in southern United States. At the index date, 17% of patients received ADA and 83% received IFX. Treatment discontinuation was observed in 52% of ADA and 45% of IFX users through 12 months postindex (mean time 19 and 22 weeks, respectively). Among discontinuers, 46% of ADA and 68% of IFX users did not restart/switch TNFi. ADA and IFX showed mean times to switch of 18 and 30 weeks, respectively. TNFi discontinuers had the lowest mean quarterly total health care cost (

THU0173 Pregnancy Outcomes in the Tofacitinib RA Safety Database Through April 2014

3,935) versus patients who initiated/switched TNFi (

Outcomes of Pregnancies With Maternal/Paternal Exposure in the Tofacitinib Safety Databases for Ulcerative Colitis

15,004). Nevertheless, discontinuers had higher UC-related hospitalization versus patients receiving therapy. CONCLUSIONS Approximately half of ADA and IFX users discontinued, with approximately half of discontinuers not restarting/switching therapies. Further investigation of treatment patterns and outcomes after TNFi discontinuation is required.

Tofacitinib is not a biologic.

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Its effect in pregnant women is of interest, as it has been shown to be foeticidal and teratogenic in both rats and rabbits at exposures 146 times and 13 times, respectively, the maximum recommended human dose. There are no adequate, well-controlled tofacitinib studies in pregnant women; per the RA clinical development programme protocols, all studies exclude pregnant subjects and require use of highly effective contraception by females with child-bearing potential, and study treatment discontinuation if a subject becomes pregnant. Objectives To understand potential effects of tofacitinib, pregnancies in the RA clinical development programme were reviewed. Methods Cases were identified from Pfizers internal safety database up to 30 April 2014, from interventional (one study is ongoing; database not locked) and non-interventional studies, plus cases from post-marketing reporting. Cases were limited to females administered tofacitinib/placebo/blinded therapy at time of conception and/or foetal subjects exposed to tofacitinib/placebo/blinded therapy through maternal exposure. Potential duplicate cases were eliminated. Remaining cases were reviewed for pregnancy-related outcomes and abnormalities; categorised as healthy newborns, spontaneous abortion, medical termination, still-birth, pending or lost to follow-up. Results 35 cases were identified. In tofacitinib RA clinical studies of 6192 subjects with 16839 patient-years exposure, there were 32 cases of maternal exposure. Subject age ranged from 22 to 40 years. Of the 32 cases, 31 received tofacitinib; 13 received 5 mg BID, 17 received 10 mg BID, and 1 received 15 mg BID. 14 of the 31 cases were also taking methotrexate (MTX). 1 subject received placebo/MTX. Pregnancy outcomes with tofacitinib were: 16 healthy newborns (including 1 low birth weight and 1 pre-term birth), 7 spontaneous abortions, 4 medical terminations, 1 congenital malformation of pulmonary valve stenosis reported in a 32-year-old subject with diabetes and hypertension, 1 ongoing pregnancy and 3 lost to follow-up; the placebo-treated subject experienced a spontaneous abortion. The remaining 3 cases receiving tofacitinib were reported from other data sources: 2 from non-interventional studies, 1 from post-marketing reporting. Foetal subjects had maternal exposure to tofacitinib. Of the 3 cases, 1 had a spontaneous abortion; outcomes were still pending for the other 2 cases. Conclusions Most cases with reported outcomes had healthy newborns. Adverse outcomes including spontaneous abortion and congenital malformation were observed in RA subjects who became pregnant during tofacitinib therapy. Pregnancy outcomes in subjects receiving tofacitinib continue to be monitored through routine pharmacovigilance and via a post-approval safety study within the Organization of Teratology Information Specialists (OTIS) registry. Acknowledgements Previously presented (Marren A et al. Arthritis Rheum 2014; 66(11): S5840 abs 1908) and reproduced with permission from Arthritis and Rheumatism. All aspects of this work were funded by Pfizer Inc. Editorial support, under the guidance of the authors, was provided by Amanda Pedder, of Complete Medical Communications, and funded by Pfizer Inc. Disclosure of Interest A. Marren Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer Inc, Y. Chen Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer Inc, D. Frazier Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer, J. Geier Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer

Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis and Psoriasis

Abstract Background Active inflammatory bowel disease increases the risk of adverse pregnancy outcomes. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). As a small molecule, tofacitinib is likely to cross the placental barrier; however, information on the effects of tofacitinib on pregnancy outcomes is limited. We report pregnancy and newborn outcomes among patients in UC clinical studies with prenatal (maternal/paternal) exposure to tofacitinib. Methods Pregnancies with maternal/paternal exposure to tofacitinib were identified and outcomes reported in 5 tofacitinib UC interventional studies (up to March 2017). Outcomes from tofacitinib rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis interventional studies, and RA noninterventional postapproval safety studies, spontaneous adverse event reporting, and registry data are also reported. Results Of 1157 patients enrolled in the UC interventional studies, 301 were women of childbearing age. Eleven cases of maternal exposure and 14 cases of paternal exposure to tofacitinib (doses of 5 mg or 10 mg twice daily) before/at the time of conception or during pregnancy were identified. Outcomes included 15 healthy newborns, no fetal deaths, no neonatal deaths, no congenital malformations, 2 spontaneous abortions, and 2 medical terminations. Outcomes across other tofacitinib studies and postmarketing cases were consistent, with a healthy newborn being the most common outcome and no fetal deaths. Conclusions Based on the limited data available, pregnancy and newborn outcomes among patients with prenatal (maternal/paternal) exposure to tofacitinib in UC studies appear similar to those reported for other tofacitinib clinical study populations and the general population.

855 Efficacy and Safety of Tofacitinib for Oral Induction Therapy in Patients With Moderate to Severe Crohn's Disease: Results of a Phase 2B Randomized Placebo-Controlled Trial

As the Global Medical Aff airs Gastroenterology Lead for tofacitinib at Pfi zer, I read with great interest the review by Dr Ungar and Dr Kopylov entitled “Advances in the development of new biologics in infl ammatory bowel disease (IBD)” [1]. In reading the article, I identifi ed a number of inaccuracies concerning tofacitinib, which I thought should be brought to the attention of the authors and your readers. Th roughout the article tofacitinib is described as being a “biologic”. Although it may be appropriate to compare the effi cacy and safety of tofacitinib to the existing biologic therapies used in IBD, tofacitinib is a synthetic small molecule JAK inhibitor and not a biologic agent. Tofacitinib was introduced along with descriptions of the biologics, including anti-integrins and ustekinumab. It would be more accurate if tofacitinib was split from these biologic agents and instead described in a separate sentence, since antiintegrins and ustekinumab are biologics and tofacitinib is not. In relation to safety events, in place of the current “Th e adverse eff ect profi le for tofacitinib appears to be similar to other biologics...”, it would be more accurate to state that “Th e adverse eff ect profi le for tofacitinib appears to be similar to that of biologics...”, thus separating tofacitinib from the biologic drug class. With respect to the discussion around immunogenicity and tofacitinib, because tofacitinib is a synthetic small molecule JAK inhibitor and not a biologic agent we would not expect there to be any immunogenicity. Hence, no specifi c studies of the immunogenicity of tofacitinib have been performed or are planned at present. Finally, we are nearing completion of a phase 3 development program of tofacitinib in ulcerative colitis [2,3] and we look forward to sharing the results of these studies with the gastroenterological community in the future.